Deoxypodophyllotoxin Induces ROSMediated Apoptosis by Modulating the PI3K/AKT and p38 MAPK-Dependent Signaling in Oral Squamous Cell Carcinoma
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Deoxypodophyllotoxin (DPT), a naturally occurring flavonolignan, possesses several pharmacological properties, including anticancer property. However, the mechanisms underlying DPT mode of action in oral squamous cell carcinoma (OSCC) remain unknown. This study aimed to investigate the anticancer effects of DPT on OSCC and the underlying mechanisms. Results of the MTT assay revealed that DPT significantly reduced the cell viability in a time- and dose-dependent manner. Flow cytometry analysis revealed that DPT induces apoptosis in OSCC cells in a dosedependent manner. Moreover, DPT enhanced the production of mitochondrial reactive oxygen species (ROS) in OSCC cells. Mechanistically, DPT induced apoptosis in OSCC cells by suppressing the PI3K/AKT signaling pathway while activating the p38 MAPK signaling to regulate the expression of apoptotic proteins. Treatment with SC79, an AKT activator, reversed the effects of DPT on AKT signaling in OSCC cells. Taken together, these results provide the basis for the use of DPT in combination with conventional chemotherapy for the treatment of oral cancer.
Abstract
Deoxypodophyllotoxin (DPT), a naturally occurring flavonolignan, possesses several pharmacological properties, including anticancer property. However, the mechanisms underlying DPT mode of action in oral squamous cell carcinoma (OSCC) remain unknown. This study aimed to investigate the anticancer effects of DPT on OSCC and the underlying mechanisms. Results of the MTT assay revealed that DPT significantly reduced the cell viability in a time- and dose-dependent manner. Flow cytometry analysis revealed that DPT induces apoptosis in OSCC cells in a dosedependent manner. Moreover, DPT enhanced the production of mitochondrial reactive oxygen species (ROS) in OSCC cells. Mechanistically, DPT induced apoptosis in OSCC cells by suppressing the PI3K/AKT signaling pathway while activating the p38 MAPK signaling to regulate the expression of apoptotic proteins. Treatment with SC79, an AKT activator, reversed the effects of DPT on AKT signaling in OSCC cells. Taken together, these results provide the basis for the use of DPT in combination with conventional chemotherapy for the treatment of oral cancer.
참고문헌 (44)
- Parkin DM, "Global cancer statistics, 2002", CA Cancer J. Clin, 55, pp.74~108 (2005)
- Herskovic A, "Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus", N. Engl. J. Med, 326, pp.1593~1598 (1992)
- Warnakulasuriya S, "Global epidemiology of oral and oropharyngeal cancer", Oral Oncol, 45, pp.309~316 (2009)
- Loike JD, "Structure-activity study of the inhibition of microtubule assembly in vitro by podophyllotoxin and its congeners", Cancer Res, 38, pp.2688~2693 (1978)
- Zilla MK, "4'-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum exhibits potential anticancer activities by altering Chk-2 signaling pathway in MCF-7 breast cancer cells", Chem. Biol. Interact, 224, pp.100~107 (2014)
- Shin SY, "Deoxypodophyllotoxin induces G2", M cell cycle arrest and apoptosis in HeLa cells, 2010, pp.287, 231~239
- Benzina S, "Deoxypodophyllotoxin isolated from Juniperus communis induces apoptosis in breast cancer cells", Anticancer Agents Med. Chem, 15, pp.79~88 (2015)
- Hu S, "Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells", Oncol. Lett, 12, pp.2918~2923 (2016)
- Wang YR, "Deoxypodophyllotoxin induces G2", M cell cycle arrest and apoptosis in SGC-7901 cells and inhibits tumor growth in vivo, 2015, pp.20, 1661~1675
- Wang Y, "Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio", Oncotarget, 6, pp.29497~29512 (2015)
- Kim SH, "Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K", AKT, Pharmacol. Rep, pp.2017, 69[DOI]
- Jung CH, "Anthricin isolated from Anthriscus sylvestris (L.) Hoffm. inhibits the growth of breast cancer cells by inhibiting Akt", mTOR signaling, and its apoptotic effects are enhanced by autophagy inhibition, 2013, pp.2013, 385219~
- Wang W, "Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K", Akt signaling pathway in human glioblastoma cells, 2019, pp.41, 2453~2463
- Yeh HT, "Flavopereirine induces cell cycle arrest and apoptosis via the AKT", p38MAPK, 2 signaling pathway in human breast cancer cells, pp.Eur. J. Pharmacol, 2019[DOI]
- Das U, "Ferulic acid enhances the radiation sensitivity of lung and liver carcinoma cells by collapsing redox homeostasis : mechanistic involvement of Akt", p38 MAPK signalling pathway, 2019, pp.53, 944~967
- Yan Y, "MiR-139-5p Targetedly regulates YAF2 and mediates the AKT", P38 MAPK signaling pathway to alleviate the metastasis of non-small cell lung cancer cells and their resistance against cisplatin, 2021, pp.13, 3639~3650
- Wang L, "Stephanthraniline A suppresses proliferation of HCT116 human colon cancer cells through induction of caspase-dependent apoptosis, dysregulation of mitochondrial function, cell cycle arrest and regulation of Akt", p38 signaling pathways, 2019, pp.44, 523~533
- Ou YW, "Mig-2 attenuates cisplatin-induced apoptosis of human glioma cells in vitro through AKT", JNK and AKT, Acta Pharmacol. Sin, pp.2014, 35[DOI]
- Zeng S, "WD40 repeat-containing 62 overexpression as a novel indicator of poor prognosis for human gastric cancer", Eur. J. Cancer, 49, pp.3752~3762 (2013)
- Raman M, "Differential regulation and properties of MAPKs", Oncogene, 26, pp.3100~3112 (2007)
- Robinson MJ, "Mitogen-activated protein kinase pathways", Curr. Opin. Cell Biol, 9, pp.180~186 (1997)
- Chan-Hui PY, "Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades", Biochem. J, 336(3), pp.599~609 (1998)
- Liu ZM, "Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells", Cell Mol. Life Sci, 64, pp.1428~1436 (2007)
- Xu N, "Akt : a double-edged sword in cell proliferation and genome stability", J. Oncol, 2012, pp.951724~ (2012)
- Aikin R, "Cross-talk between phosphatidylinositol 3-kinase", AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets, 2004, pp.145, 4522~4531
- Liao Y, "Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis", Mol. Cell Biol, 23, pp.6836~6848 (2003)
- Molinolo AA, "Dysregulated molecular networks in head and neck carcinogenesis", Oral Oncol, 45, pp.324~334 (2009)
- Tan W, "Anti-cancer natural products isolated from chinese medicinal herbs", Chin. Med, 6, pp.27~ (2011)
- Gniadecki R, "Role of mitochondria in ultraviolet-induced oxidative stress", J. Cell Biochem, 80, pp.216~222 (2000)
- Su YT, "Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway", Biochem. Pharmacol, 70, pp.229~241 (2005)
- Julien Coulie, "Molecular pathways and possible therapies for head and neck vascular anomalies", Journal of Oral Pathology & Medicine, 51(10), pp.878~887 (2022), Wiley[DOI]
- Lu Y, "Anlotinib suppresses oral squamous cell carcinoma growth and metastasis by targeting the RAS protein to inhibit the PI3K", Akt signalling pathway, 2021, pp.2021, 5228713~
- Jeon YJ, "Esculetin induces apoptosis through EGFR", PI3K, J. Cell Biochem, pp.2016, 117[DOI]
- Engelman JA, "The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism", Nat. Rev. Genet, 7, pp.606~619 (2006)
- Dey S, "Critical pathways of oral squamous cell carcinoma : molecular biomarker and therapeutic intervention", Med. Oncol, 39, pp.30~ (2022)
- Boldt S, "The role of MAPK pathways in the action of chemotherapeutic drugs", Carcinogenesis, 23, pp.1831~1838 (2002)
- Dhillon AS, "MAP kinase signalling pathways in cancer", Oncogene, 26, pp.3279~3290 (2007)
- Chang L, "Mammalian MAP kinase signalling cascades", Nature, 410, pp.37~40 (2001)
- Boutros T, "Mitogen-activated protein(MAP)kinase", MAP kinase phosphatase regulation : roles in cell growth, death, and cancer, 2008, pp.60, 261~310
- Murray AW, "Recycling the cell cycle : cyclins revisited", Cell, 116, pp.221~234 (2004)
- Akgul C, "Mcl-1 is a potential therapeutic target in multiple types of cancer", Cell Mol. Life Sci, 66, pp.1326~1336 (2009)
- Okaro AC, "The expression of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1 in benign, dysplastic, and malignant biliary epithelium", J. Clin. Pathol, 54, pp.927~932 (2001)
- Chetoui N, "Down-regulation of mcl-1 by small interfering RNA sensitizes resistant melanoma cells to fas-mediated apoptosis", Mol. Cancer Res, 6, pp.42~52 (2008)
- Andersson Y, "Downregulation of the antiapoptotic MCL-1 protein and apoptosis in MA-11 breast cancer cells induced by an anti-epidermal growth factor receptor-Pseudomonas exotoxin a immunotoxin", Int. J. Cancer, 112, pp.475~483 (2004)
